Malaria is a life-threatening mosquito-borne disease caused by parasites of the genus Plasmodium. Infection exacts a significant toll on human public health with about 200 million new cases and greater than 500,000 deaths reported each year. Despite decades of research, the immune mechanisms responsible for protection against malaria are poorly understood. In rodent models of malaria, a variety of immune proteins called cytokines have been shown to either promote or suppress protective immunity. While the cytokine interleukin-3 (IL-3) clearly promotes host defense against some intestinal parasites, no similar function for IL-3 has been reported in the pathophysiology of malaria. We recently demonstrated that IL-3 plays a novel role in susceptibility to malaria; mice deficient in IL-3 had lower levels of parasites in the blood and survived longer than similarly infected mice with IL-3. Thus, genetic deficiency of IL-3 improves the outcome of infection. Our preliminary data is consistent with the hypothesis that IL-3 exacerbates disease by promoting the overproduction of other cytokines, such as interferon-? (IFN-?) and mast cell-derived Flt3 ligand, and by modulating the function of other immune cells. Furthermore, our findings suggest for the first time that cells other than T lymphocytes may represent an important, clinically relevant source of IL-3. In this proposal, we will develop new experimental tools and approaches to test these hypotheses. In Aim 1 we will use IL-3- deficient mice and other mouse strains to assess the mechanisms by which IL-3 regulates resistance to acute blood-stage malaria infection caused by lethal malaria parasites. For these studies we will examine the ability of IL-3 to regulate the production of IFN-? and to promote malaria-induced increases in mast cell-derived Flt3 ligand. In Aim 2 we will use IL-3-deficient mice to assess the extent to which IL-3 influences the course and outcome of disease in chronic or long-term malaria infection induced by nonlethal parasites, and in an experimental model of severe malaria that leads to brain inflammation. In Aim 3, we will create a novel IL-3 reporter mouse that will allow identification and monitoring of IL-3-producing cells throughout the course of malaria infection. The results of these proposed studies will not only fill a void in our understanding of malaria immunity, but will identify novel aspects of IL-3 production and function that may be of consequence in other IL-3-dependent disease processes.